Article Mesoionic Carbene-Breslow Intermediates As Super Electron Donors: Application to the Metal-Free Arylacylation of Alkenes

Article Mesoionic carbene-Breslow intermediates as super electron donors: Application to the metal-free arylacylation of alkenes

Wei Liu, Adam Vianna, Zengyu Zhang, ..., Mohand Melaimi, Guy Bertrand, Xiaoyu Yan

[email protected] (G.B.) [email protected] (X.Y.)

Highlights Breslow intermediates derived from mesoionic carbenes are super electron donors

A mesoionic-carbene-catalyzed arylacylation of alkenes is described

Facile construction of complex carbonyl compounds from simple substrates

Breslow intermediates derived from mesoionic carbenes (BIMICs) are highly reductive species able to reduce iodoarenes under ambient condition. The reductive power of BIMICs allows for the use of mesoionic carbenes as powerful catalysts in the inter- and intramolecular arylacylation of alkenes.

Liu et al., Chem Catalysis 1,1–11 June 17, 2021 ª 2021 Elsevier Inc. https://doi.org/10.1016/j.checat.2021.03.004 Please cite this article in press as: Liu et al., Mesoionic carbene-Breslow intermediates as super electron donors: Application to the metal-free arylacylation of alkenes, Chem Catalysis (2021), https://doi.org/10.1016/j.checat.2021.03.004

Article Mesoionic carbene-Breslow intermediates as super electron donors: Application to the metal-free arylacylation of alkenes

Wei Liu,1 Adam Vianna,2 Zengyu Zhang,1 Shiqing Huang,1 Linwei Huang,1 Mohand Melaimi,2 Guy Bertrand,2,3,* and Xiaoyu Yan1,*

SUMMARY The bigger picture Classical N-heterocyclic carbenes (NHCs), such as thiazolylidenes, N-Heterocyclic carbenes (NHCs) 1,2,4-triazolylidenes, and imidazol(in)-2-ylidenes, are powerful or- have been demonstrated to be ganocatalysts for aldehyde transformations through the so-called powerful organocatalysts for Breslow intermediates (BIs). The reactions usually occur via elec- carbonyl transformations via the tron-pair-transfer processes. In contrast, the use of BIs in single- so-called Breslow intermediates electron transfer (SET) pathways is still in its infancy, and the scope (BIs). Recently, NHC-catalyzed is limited by the moderate reduction potential of BIs derived from reactions via single-electron classical NHCs (ca. À1.0 V versus standard calomel electrode transfer (SET) pathways have been [SCE]). Here, we report that BIs from 1,2,3-triazolylidenes, a type developed but still suffer from the of mesoionic carbene (MIC), have a reduction potential as negative limitation of moderate reduction as À1.93 V versus SCE and thus are among the most potent organic potential of BIs. In this paper, reducing agents reported to date. They are reductive enough to taking advantage of highly undergo SET with iodoarenes, which allows the highly efficient inter- reductive MIC-derived BIs, we and intramolecular MIC-catalyzed arylacylation of styrenes and describe the three-component alkenes, respectively. coupling reaction of iodoarenes, alkenes, and aldehydes catalyzed INTRODUCTION by mesoionic carbenes (MICs). This reaction affords various Over the past decades, N-heterocyclic carbenes (NHCs) have been demonstrated to substituted ketones and even be powerful organocatalysts for aldehyde transformations.1–6 The umpolung of al- polycyclic ketones with readily dehydes by NHCs7 through the formation of nucleophilic Breslow intermediates available substrates. (BIs) was later extended to provide other reactive intermediates, such as acyl azo- liums, enolates, and homoenolates.8–12 These intermediates react with diverse elec- trophilic and nucleophilic coupling partners via electron-pair-transfer processes. In contrast, NHC-catalyzed reactions via single-electron transfer (SET) pathways are still in their infancy.13–15 In 2008, Studer and co-workers reported the NHC-catalyzed oxidation of aldehydes by TEMPO via a SET process (Figure 1).16 Other oxidants, such as nitroarenes, nitroalkenes, CX4,C2Cl6, and sulfonic carbamate, were also employed to achieve oxidative reactions of aldehydes.17–21 Recently, an important breakthrough has been reported by Ohmiya, Nagao, and co-workers, who showed that redox-active esters could be employed as both SET oxidants and alkylating reagents.22,23 The same group also described a three-component alkylacylation reaction of alkenes via a radical relay strategy,24 andtheLigroupachievedtheNHC- catalyzed radical acylfluoroalkylation of olefins with the Togni reagent or polyfluor- oalkyl halides.25 Ye and co-workers described g-andε-alkylation with alkyl radicals, in which an activated alkyl halide was employed as SET oxidant and alkylating reagent.26 Hongandco-workersreportedtheNHC-catalyzedradicalcouplingofalde- hydes and Katritzky pyridinium salts.27 However, as a result of the moderate reduction potential of BIs derived from classical NHCs (ca. À1.0 V versus standard calomel electrode [SCE]),28–30 these SET catalyzed reactions required a relatively strong

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Figure 1. BIs for SET reactions (A) Reduction potential of known BIs and their SET partners. (B) Breslow intermediates derived from mesoionic carbenes (BIMICs). (C) Three-component MIC-catalyzed arylacylation of alkenes. oxidant to ensure the electron-transfer process, which dramatically limits the scope of the reactions. For much less oxidative substrates, BIs with more negative reduction potentials are needed. Recently, we reported the formation of BIs derived from mesoionic carbenes (BIMICs) and their application to the catalytic H/D exchange of aldehydes.31 This class of BIs was found to be far more electron rich than any others previously known and should thus be much more reductive. Herein, we describe the electrochemistry of BIMICs, which have a reduction potential as negative as À2.49 V versus Fc/Fc+ (calculated as À1.93 V versus SCE). The oxidation product, namely the radical form of a deprotonated BIMIC, was unambiguously characterized by a single-crystal X-ray diffraction study. This type of BI can be clas- siﬁed as a new organic super electron donor32,33 and is reductive enough to undergo SET with iodoarenes. This is demonstrated by the highly efﬁcient mesoionic carbene (MIC)-catalyzed arylacylation of alkenes. 1Department of Chemistry, Renmin University of China, Beijing 100872, People’s Republic of China RESULTS AND DISCUSSION 2UCSD-CNRS Joint Research Laboratory (UMI Initially, we investigated the electrochemistry of BIMIC 3a, which was prepared by 3555), Department of Chemistry and Biochemistry, University of California, San Diego, 34–37 addition of benzaldehyde to MIC 2a, generated by deprotonation of 1a (Fig- La Jolla, CA 92093-0358, USA ure 2A). The cyclic voltammogram of 3a shows an irreversible redox process be- 3Lead contact ∙ tween 3a and 4a with an anodic peak potential Epa = À2.49 V and a corresponding *Correspondence: [email protected] (G.B.), cathodic peak potential Epc = À2.59 V (Figure 2F). This is in agreement with an EC [email protected] (X.Y.) process38 in which the oxidation of 3a is immediately followed by the easy https://doi.org/10.1016/j.checat.2021.03.004

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Figure 2. Synthesis and characterization of 3a and 4a∙ (A) Synthesis of 3a. ∙ (B) Synthesis of 4a . ∙ (C) Solid-state structure of 4a . ∙ (D) EPR of 4a (top, experimental; bottom, simulated). ∙ (E) Electron spin density of 4a . (F) Cyclic voltammograms of 3a in tetrahydrofuran (THF) (+(nBu)4NPF6 0.1 mol/L). ∙ (G) Cyclic voltammograms of 4a in THF (+(nBu)4NPF6 0.1 mol/L). + (H) Cyclic voltammograms of 4a in THF (+(nBu)4NPF6 0.1 mol/L). + *Refer to the redox of in-situ-generated impurity 1a. (Scan rate: 100 mV/s; E versus Fc/Fc .)

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Figure 3. Proposed reaction pathway for the MIC-catalyzed arylacylation of alkenes

∙ deprotonation of 3a to generate 4a .29 To confirm this redox process, we prepared ∙ + the radical form 4a by reducing the deprotonated BIMIC 4a with KC8 in tetrahydro- ∙ furan (Figure 2B). The structure of 4a was unambiguously characterized by X-ray diffraction analysis (Figure 2C) and electron paramagnetic resonance (EPR) (Fig- ure 2D). Compared with other acyl-carbene radicals derived from NHCs and CAACs,39–41 the C(carbene)–C(acyl) bond is slightly longer, whereas the dihedral angle between the carbene ring and the acyl moiety is larger. We performed density functional theory (DFT) calculations at the B3LYP-D3(BJ)/6-311G** level of theory to ∙ ∙ gain more insight into the electronic structure of 4a . The SOMO of 4a is mainly located on the p* orbital of the triazole ring and carbonyl group (see supplemental information), whereas the spin density is mainly located on N1 and N2 with some ∙ contribution on C2, C40, and O1 (Figure 2E). As expected, EPR spectra of 4a in benzene solution featured a strong signal centered at g = 2.003 with hyperfine coupling with two nitrogen nuclei (aiso = 6.68 G). In agreement with DFT calculations, the small hyperfine coupling constants indicate a strong delocalization of the unpaired elec- ∙ tron. The cyclic voltammogram of 4a also shows two irreversible peaks (one oxidation peak at À2.46 V and one reduction peak at À2.63 V), which affords further evi- ∙ dence of the process between 3a and 4a (Figure 2G). In addition, one set of reversible peaks at E1/2 = À1.53 V was observed, corresponding to the reversible ∙ process 4a /4a+. To further confirm our hypothesis, we also carried out a cyclic voltammogram of 4a+, which showed two irreversible peaks and one set of reversible ∙ peaks (Figure 2H). It is noteworthy that the reversible process 4a /4a+ was not observed in Figure 2F, which is due to the instability of 4a+ in the presence of excess of highly reductive 3a.29

Fromtheseresultsitcanbeconcludedthat3a is the most reductive BI known so far and is among the most potent organic reducing agents (in the ground state).42 Thus, we hypothesized that this type of BI derived from MICs should be able to reduce haloarenes under mild conditions. To prove it, we designed a catalytic radical reaction, namely the three-component arylacylation of alkenes with a MIC as catalyst (Fig- ure 3). MICs 2, generated in situ by deprotonation of triazoliums 1, should react

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Figure 4. Optimization of the MIC-catalyzed arylacylation Mes, 2,4,6-trimethylphenyl; Dipp, 2,6-diisopropylphenyl; IMes, 1,3-bis(2,4,6-trimethylphenyl) imidazolinylidene. Reaction conditions: 7 (0.9 mmol), 8 (0.9 mmol), 9 (0.5 mmol), 1 (0.05 mmol), base (0.75 mmol), and anhydrous tBuOMe(1.5mL)for4hat30C. The reactions were carried out in a 25 mL Schlenk tube. aNMR yields (isolated yields are given in parentheses). btBuONa instead of tBuOK. cThe mixture was stirred at 0C. dThe mixture was stirred at 50C.

with an aldehyde to give the BIMIC 3, which should be deprotonated to its enolate form and then undergo a SET process with an aryl iodide, giving a persistent radical ∙ 4 and a transient aryl radical.43 The latter should add to the alkene to yield a very ∙ reactive alkyl radical 5, which could attack 4 , regenerating the MIC catalyst and affording the arylacylated alkene 6.

To check this hypothesis, we treated a mixture of 4-methoxybenzaldehyde 7a, iodo- t benzene 8a, and styrene 9a in BuOMe with a catalytic amount of different triazolium t salts (1a-1g) in the presence of BuOK as a base (Figure 4, entries 1–7). When triazolium salt 1a was used, the arylacylation product 6aaa was formed in 13% yield. 4-Un- substituted triazolium salts 1b and 1c gave better yields (41% and 51%,

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ll Article respectively). Low yields were observed for 4-substituted triazolium 1d and 1e.Sur- prisingly, 4-ester substituted triazolium with Dipp substituents (1f)gavean85% yield, whereas the Mes analog 1g only afforded a rather low yield. Solvent screening t t showed BuOMe to be the best choice (entries 8–11). Using BuONa instead of t BuOK led to much lower yields (entry 12). Temperature variation also lowered the yields (entries 13 and 14). Importantly, other types of NHC precursors, such as imidazolium 1h, thiazolium 1i, and 1,2,4-triazolium 1j, were ineffective for this reaction t (entries 15–17). The control experiment performed in the presence of BuOK but in the absence of the MIC catalyst 1f was also carried out, and no reaction was t observed (entry 18). This result ruled out the hypothesis that BuOK acted as a catalyst or radical initiator in this reaction.44,45 In addition, the reaction was not inﬂu- enced by light. Either in the presence of light (day light, blue light, green light) or in the absence of light, similar yields were obtained.

The scope of the MIC-catalyzed three-component arylacylation reaction was investigated under the optimized conditions as shown in Figure 5.Aromaticaldehydes with electron-donating groups afforded the arylacylation products in high yields (6aaa-6daa), whereas an electron-deficient aromatic aldehyde led to a lower yield (6eaa). meta- and ortho-Substituted aldehydes afforded the corresponding products in 51% and 42% yield, respectively (6faa and 6gaa), which shows that the steric hindrance has a significant influence on the reaction. Heterocyclic aryl aldehydes gave 6haa–6kaa in 30%–61% yields. A variety of electron-donating and electron-withdrawing groups were tolerated on aryl iodides (6aba–6aga). 2-Iodo- naphthalene afforded the desired product in 45% yield (6aha). For heteroaromatic iodides, such as N-methyl-5-iodoindole, 2-iodopyridine, and 3-iodopyridine, the MIC-catalyzed reactions were accomplished in 43%–65% isolated yields (6aia– 6aka). Substituted styrenes, such as 4-methoxystyrene, 4-methylstyrene, 3-methylstyrene, 4-bromostyrene and 2-vinylnaphthalene, were tolerated under the reaction conditions (6aab–6aaf). When 1-phenyl-1,3-butadiene was used instead of styrene, both 1,2-addition and 1,4-addition products were formed in a 2:1 ratio. Interestingly, when 2,3-dimethyl-1,3-butadiene was employed, only the 1,4-addition product was observed in high yield, whereas some base-induced isomeriza- tion occurred. In all cases, some amount of diarylethanes, benzyl alcohols, and esters were formed as side products. The former came from H-abstraction of 5, whereas the latter resulted from reduction of aldehydes by BIMIC. Consequently, much lower yields were obtained with bulky substrates and easily reducible substrates; in addition, the process is not efficient with aliphatic aldehydes and alkenes.

To further extend this reaction, we considered compounds 10 featuring a tethered aryliodideandanalkene.Inallcases,highyieldswereobservedfortheintramo- lecular arylacylation reaction (Figure 6). 1-Allyloxy-2-iodobenzene 10a reacted with different aldehydes, affording the corresponding products in 65%–84% isolated yields (11aa–11ca and 11ja). Other substrates with different tether atoms and substituents were also compatible in the cyclization reaction. 1-(Methylally- loxy)-2-iodobenzene 10b gave the 11ab in 72% yield. Nitrogen-tethered aryl iodides and alkene moieties (10c–10e) afforded the products 11ac–11ae in 65%– 76% yields. It is noteworthy that allenes can be employed in this reaction. 2-Iodo- phenyl allenyl ether gave benzofuran 11af in 78% yield. 2-Iodophenyl homoallyl ether 10g gave the six-membered chromane derivative 11ag in 79% yield. This reaction can be further expanded to the construction of polycyclic compounds. The annulation of 2-iodophenyl-cyclohex-3-enyl ether led to tricyclic ketone 11ah as a single diastereomer, the structure of which was further conﬁrmed by X-ray

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Figure 5. Substrate scope of the MIC-catalyzed arylacylation of alkenes Reaction conditions: aldehyde 7 (0.9 mmol), aryl iodide 8 (0.9 mmol), alkene 9 (0.5 mmol), 1f (0.05 mmol), and tBuOK (0.75 mmol) in anhydrous tBuOMe (1.5 mL) at 30C for 4 h; isolated yields are based on alkenes. a4-Phenyl-1,3-butadiene was employed, and the isomer ratio is given in parentheses. b2,3-Dimethyl-1,3-butadiene was employed, and the isomer ratio is given in parentheses.

diffraction analysis. The annulation of 2-iodobenzyl-cyclohex-3-enyl ether 10i gave 11ai in 61% yield as two diastereomers in a 1:1 ratio. Interestingly, the reaction of 2- iodophenyl-cyclohexen-1-ylmethyl ether 10j gave spirocyclohexane 11aj in 21% yield as a single diastereomer.

Finally, we performed a radical clock reaction under the standard reaction conditions by using cyclopropylstyrene as the substrate. The reaction gave the cyclopropyl ring-opening adduct 12 in 25% yield, which conﬁrmed the radical mechanism of the MIC-catalyzed arylacylation (Figure 7).

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Figure 6. Substrate scope of the MIC-catalyzed annulation and cascade acylation Reaction conditions: aldehyde 7 (0.9 mmol), o-iodophenyl alkene 10 (0.5 mmol), 1f (0.05 mmol), and tBuOK (0.75 mmol) in anhydrous tBuOMe (1.5 mL) at 30Cfor4h. aIsolated yields are based on alkenes. bSingle isomer; the stereochemistry was not deﬁned.

Conclusions It was known that haloarenes could stoichiometrically be activated by super electron donors, but their functionalization was rarely reported under metal-free conditions.42,46,47 Intramolecular arylacylation reactions have only been achieved with Pd and Ni catalysts.48–51 In this paper, we have shown that BIMICs are among the most potent organic reducing agents reported to date in the ground state

Figure 7. Radical clock reaction

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(À2.49 V versus Fc/Fc+). This allows BIMICs to activate iodoarenes under mild conditions and to promote the catalytic inter- and intramolecular arylacylation of alkenes, which affords a number of substituted ketones and even polycyclic ketones. Importantly, triazolium salts of type 1, as well as the ensuing MICs, are readily available in large quantities with a variety of N- and C-substituents, allowing for a ﬁne- tuning of their reduction potential and steric environment.34,35 The strong reduction potential of BIMICs should allow for the activation of more challenging bonds than classical NHCs, such as thiazolylidenes, 1,2,4-triazolylidene, and imidazol(in)ylidenes, can do. Other types of MICs are either already known, such as the so-called abnormal NHCs,52,53 or can certainly be prepared and thus are interesting targets for SET processes.

EXPERIMENTAL PROCEDURES Full experimental procedures are provided in the supplemental information.

Resource availability Lead contact Further information and requests for resources should be directed to and will be ful- ﬁlled by the lead contact, Guy Bertrand ([email protected]).

Materials availability All other data supporting the ﬁndings of this study are available within the article and the supplemental information or from the lead contact upon reasonable request.

Data and code availability Data relating to the materials and methods, experimental procedures, DFT calculations, and NMR spectra are available in the supplemental information.Crystallo- graphic data of substrates 4a∙ (CCDC: 2047374) and 11ah (CCDC: 2043281) can be obtained free of charge from the Cambridge Crystallographic Data Center (http://www.ccdc.cam.ac.uk/structures/). All other data are available from the authors upon reasonable request.

SUPPLEMENTAL INFORMATION Supplemental information can be found online at https://doi.org/10.1016/j.checat. 2021.03.004.

ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (21602249), the Fundamental Research Funds for the Central Universities and the Research Funds of Renmin University of China (program 20XNLG20), the US Depart- ment of Energy, Ofﬁce of Science, Basic Energy Sciences, Catalysis Science Program under award no. DE-SC0009376, and the American Chemical Society Petroleum Research Fund (60776-ND1).

AUTHOR CONTRIBUTIONS W.L., Z.Z., and L.H. conducted the experiments and analyzed the data. S.H. carried out the computational analyses. A.V. and M.M. synthesized and characterized the BIMIC radical form. G.B. and X.Y. supervised the project. All authors discussed the results and wrote the paper.

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DECLARATION OF INTERESTS The authors declare no competing interests.

Received: January 15, 2021 Revised: March 4, 2021 Accepted: March 12, 2021 Published: April 2, 2021

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